The overall goal of the Baltimore Huntington's Disease Center is to conduct interdisciplinary studies of the clinical and basic science of HD in order clarify pathogenesis, facilitate the design and interpretation of clinical trials, and identify and characterize therapeutic targets. Project 1 will identify factors, including CAG repeat length, that influence clinical presentation and longitudinal progression, in order to clarify HD pathogenesis, and facilitate the design and interpretation of future clinical trials. Project 1 will also conduct clinical-pathologic studies. Project 2 will use MRI technology to chart the cross sectional and longitudinal course of brain changes at all stages of HD, including change in the striatum and cerebral cortical gray and white matter, as well as functional studies. Project 3 will focus on the earliest identifiable changes that may initiate pathogenic processes, especially post-translational modification of huntingtin. Proteolytic cleavage and phosphorylation of huntingtin will be studied in cell and mouse models, and in HD post mortem tissue. These projects will be supported by four cores. Core A will provide administration and overall scientific direction. Core B will provide longitudinal clinical and neuropsychological assessments of individuals with HD or at risk for HD, and infrastructure for imaging, genetic and other assessments for use in Projects 1 and 2 and Core D. Core C will provide postmortem examination and diagnosis, and tissue for Project 3, and support the quantitative clinical pathologic studies in Project 1. Core D will provide genetic diagnosis of HD and HD-related disorders, and accurate data on CAG expansion length for use by all projects. Project 1 Title: Clinical progression and pathologic correlates of Huntington's disease PI: Adam Rosenblatt, MD DESCRIPTION (provided by applicant): The overall goal of Project 1 is to facilitate the discovery and implementation of rational therapy for HD by identifying the factors that drive clinical presentation and longitudinal progression, in order to understand its pathogenesis and discover targets for intervention. This will be accomplished by examining three major sets of hypotheses. In Aim 1 we are testing the hypothesis, supported by our preliminary data, that the rate and trajectory of longitudinal progression, whether in the motor, cognitive or functional spheres, and the nature of the clinical presentation, as exemplified by the relative prominence of chorea and motor impairment, is predicted by the size of the CAG expansion. In Aim 2 we are testing the hypothesis, using instruments developed in Core B and new imaging techniques developed by Project 2, that the cognitive and behavioral syndrome of HD is not produced solely by changes in the striatum but that cortical changes are also an important determinant, and further that difficulties in executive function, apathy, irritability and disinheriting can be related to frontal pathology, while problems in spatial memory are associated with the parietal lobes. In Aim 3 we are testing two different hypotheses. First, using stereo logic techniques developed in Core C, we are testing the hypothesis that different aspects of the motor presentation of HD, specifically chorea and motor impairment, are caused by loss of neurons in different parts of the brain. We predict that motor impairment, but not chorea, will be associated with loss of neurons in the putamen, while chorea may be associated with neuronal loss in the subthalamic nucleus. We will also test the alternative, or complimentary hypothesis that motor impairment in HD will be associated with cell loss, reflected in the density of intranuclear inclusions, while chorea may associate with the density of cytoplasmic inclusions, reflecting cell dysfunction.